PROJECT SUMMARY/ABSTRACT The overall objective of this K08 Mentored Clinical Scientist Career Development Award Application is to provide Dr. Moran with the essential skills and training necessary to become an independent physician scientist. Dr. Moran and his mentor have designed a training plan with a rigorous research component along with didactic instruction to establish the thought processes and principles necessary for successful career development. With the knowledge and training acquired during this proposal, Dr. Moran will be well positioned to conduct innovative translational studies into the mechanisms of environment-mediated lung diseases. Endotoxin (lipopolysaccharide, LPS) and ozone are common airborne pollutants that cause significant respiratory disease morbidity and mortality. Lung innate immune cells, including alveolar macrophage (AM), play a critical role in mediating inflammatory responses to inhaled endotoxin and ozone. The key molecules that regulate innate immune responses to inhaled pollutants, and thus prevent pollutant-induced lung injury, remain undefined. Dr. Moran has recently reported that neuropilin-2 (NRP2)?a pleiotropic protein with membrane-bound and soluble isoforms?is upregulated by human and murine AM following LPS stimulation. Interestingly, myeloid-specific ablation of NRP2 augments LPS-induced airway inflammation, indicating that NRP2 negatively regulates inflammatory responses in the lungs. In addition, preliminary studies show that ozone exposure increases NRP2 expression in murine lungs, suggesting that upregulation of NRP2 may be a general anti-inflammatory response to inhaled environmental pollutants. For this proposal, Dr. Moran will investigate the mechanisms by which NRP2 negatively regulates pollutant-mediated airway inflammation. In Aim 1, he will determine if membrane-bound NRP2 directly inhibits LPS- and ozone-mediated activation of human and murine AM. In Aim 2, he will determine if a soluble isoform of NRP2 attenuates LPS- and ozone- induced airway inflammation in mice. In Aim 3, he will begin to translate his finding to humans by determining the effects of inhaled LPS on sputum and serum NRP2 levels in healthy volunteers. These studies will be the first to investigate the immunoregulatory role of NRP2 in pollutant-triggered airway inflammation, and may reveal a new therapeutic target and/or biomarker for environmental airways injury.